Cyclopropyl amide

Recently, the total synthesis of grenadamide, a naturally occuring chiral cyclopropyl amide isolated from marine cyanobacterium Lyngbya majuscula <1998JNP681>, was published employing the aforementioned diastereoselective cyclopropanation protocol as the key step in the synthesis <20060BC323>. 

A vast number of A-cyclopropyl amide and carbamate derivatives have been converted to the corresponding cyclopropylamines, often in excellent yield. This topic will not be covered extensively here, but the various conditions employed to bring about the reactions are listed below. Amides afford amines when treated with a strong mineral acid, usually hydrochloric acid, or a base such as methylamine followed by potassium hydroxide. Carba-... 

A specific example of prudent hit-to-lead design is illustrated in the development of soluble epoxide hydrolase inhibitors by Tanaka et al. [16]. By placing more emphasis on ligand efficiency of hits rather than the better absolute potency of larger and more lipophilic hits, they explored the SAR of the cyclopropyl amide shown in Figure 17.5. While the hit compound has only 0.5 micromolar activity, it has quite good ligand efficiency and is amenable to rapid... 

The photochemical rearrangement of enamides to vinylogous amides was described (65],652). Rearrangement of cyclopropyl ketimines to enamines with acid was applied to syntheses of myosamine, apoferrosamine, mesembrine, and desmethoxymesembrine (653-656). 

Aryl 3-chloropropyl sulfones 231 were shown to cyclize to aryl cyclopropyl sulfones upon treatment with t-BuOK in r-butanol283 or with sodium amide in 1,2-dimethoxyethane284. Bird and Stirling285 investigated the reaction of aryl 3-chloropropyl... 

Allyl- -diathylester 204 Allyl-(2-methyl-allyl)- -diathylester 202 -amid-nitril (2,2-disubst.) 113 Amino- -diathylester 613 Benzyl- -diathylester 204, 208, 210 Benzyl- -dinitril 559 Benzyliden- -diathylester 208, 210 Benzyliden- -diathylester-nitril 206 Benzyliden- -dinitril 559, 643 ter.-Butyl- -nitril 114 Cyclohexyl- -athylester-nitril 206 Cyclohexyl- -diathylester 204 Cyclohexyl- -dinitril 559 Cyclohexyliden- -athylester-nitril 206 Cyclohexyliden- -dinitril 559 (1-Cyclopropyl-athyliden)- -dinitril 666 Diathyl- -amid-nitril 113 -diester 640... 

Two equiv. of 6,6-di(cyclopropyl)fulvene react at 60 °C over a period of a week with Ca[N(SiMe3)2]2-(THF)2 bis in THF to yield the metallocene 170. The heteroleptic amido complex 171 is detected as an intermediate with 111 and 13C 1H NMR spectroscopy. A 1 1 reaction of the calcium amide and 170 also produces 171 in solution, an equilibrium involving these three derivatives exists (Equation (30)). The calcocene 170 crystallizes at — 20 °C from THF as colorless cuboids. The metal center is surrounded by the four ligands in a distorted tetrahedral manner, and the cyclopentadienyl group and the propylidene fragment are coplanar with each other.393... 

Rearrangements Emmons found the reagent suitable for Beckmann rearrangements giving water soluble amides. Thus methyl cyclopropyl ketoxime in the medium of 1, 2-dimethoyethane was treated under reflux with stirring with trifluoroacetic anhydride in 1 hr. and refluxed for 1 hr. more. The cyclopropylamine was obtained. 

Caubere et al. [64, 65] also employed enolates as nucleophiles to intercept the intermediates produced from 32a and the mixture of sodium amide and a sodium enolate. Scheme 6.12 illustrates the results obtained by using the enolates of cyclohexanone and cyclopropyl methyl ketone. The former furnished only the ketone 43 in hexamethylphosphoric triamide as solvent, but almost exclusively the cyclobuta-... 

Thus, allyl telluronium ylides generated in situ from the corresponding telluronium salts in the presence of Li salts react with a,)3-unsaturated esters and amides to afford trans-2-vinyl-/rany-3-substituted cyclopropyl compounds in high yieds. 

In contrast to the above-described results obtained with a, 8-unsaturated esters and amides, a, -unsaturated ketones submitted to a similar reaction give rise to cti-2-vinyl-fran,y-3-substituted cyclopropyl ketones with high stereoselectivity and high yields. ... 

Simple side-chain reactions of 1,2-dithiin diols have been conducted. Besides the formation of esters, ethers (R = Me, Et, 7-Pr, cyclopropyl, Ph, pyridyl, cyclopentyl), and thioethers (R = H, TBDMS R = 4 -(4-hydroxyphenyl)-l//-tetrazole-5-thiol), selective oxidation of the primary alcohol groups in the presence of the 1,2-dithiin heterocycle could be readily achieved (Scheme 36) <1995JME2628, 1994SL201>. Additionally, amides, ureas, and carbamates of the dithiin diol were synthesized <1995JME2628>. 

Another important line of research was the synthesis of 3,4,5-trialkoxybenzamides, as some of these derivatives showed outstanding psychopharmacological activities. Among these compounds, 4-(3,4,5-trimethoxybenzoyl)morpholine (named Trioxazin) was introduced as a minor tranquilizer, N-cyclopropyl-4-(decyloxy)-3,5-dimethoxybenz-amide (Denegit) as an antiepileptic agent, and 2-(l-pyrrolidinyl)ethyl 4-butoxy-3,5-dimethoxybenzoate (Vasopenton) as a spasmolytic, for use in clinical practice. 

Thus, our studies examined the effect of these incorporations on H3 receptor affinity by making ligands that could be envisioned synthetically by modifying the two structural features A and B of 29 illustrated in figure 18 A 2-carbon straight chain vs trans cyclopropyl ring and B amide-oxime array vs the other spacers depicted in figure 17. For the purpose of these SAR studies, we used the cyclohexyl or phenyl tail which were available from commercially available (S)-N-Boc-cyclohexylalanine or (S)-N-Boc-phenylalanine. 

The synthesis of cyclopropyl compounds containing the olefin replacement for the amide bond but without the additional primary chiral amino substituent were prepared by modified Julia olefination procedures. Addition of the benzothiazole sulfone 44 to aldehyde 39 gave trityl protected olefins in a 1 1 ratio. These... 

Such substitutions using lithium amides, secondary and in some cases tertiary amines as nucleophiles, have been introduced in early sixties as the first expedient method for this unique class of compounds. It is relevant that / ,/ -difluoro- and chlorofluorole-fins readily available through modified Wittig reaction from aldehydes constitute also good ynamine precursors. In the past decade, however, the more versatile lithium aminoacetylide method has gained more prominence. Substitution reactions are still used, among others, for phenyl, tert.-butyl, cinnamyl and cyclopropyl ynamines. 

Again, the forward reaction was best done using malonate chemistry but the variant with malonic acid was used. The cyclopropyl amine unit (here as an amide) is present in many biologically active compounds and the free amine is available. 

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